Interferon is a glycoprotein derived from most of the cells having a nucleus, and regulates immune responses. Interferon elicits a series of intracellular responses and immunoregulatory responses by binding to a specific receptor on the cell surface of the cell membrane. The intracellular responses may include induction of the activation of specific enzymes, etc., and the immunoregulatory responses may include enhancing the phagocytosis activity of macrophages and the cytotoxicity of lymphocytes against target cells.
Interferons are classified into type 1 and type 2 based on the physiochemical and functional properties. Type 1 interferons include interferon-α, -β, -τ, and -ω; and type 2 interferons include interferon-γ. Among them, interferon-β is a protein of a single chain, which has a molecular weight of approximately 20 kDa, contains a sugar of about 20%, and is composed of 166 amino acids.
Currently, recombinant interferon-β is used as a therapeutic agent or adjuvant for a variety of diseases and, the representative disease for which interferon-β is used as a therapeutic agent is multiple sclerosis, an autoimmune disease (Airas L. et al., Ann NY Acad Sci., 2007, September: 1110:641-8).
Recently, researches have been made to enhance immune responses using an RNA oligonucleotide. U.S. Patent Application Publication No. 2012/0288476 discloses that an uncapped oligonucleotide having a phosphate group at the 5′-end can enhance the expression of type 1 interferon, interleukin-18, and interleukin-1β, etc.
In addition, U.S. Patent Application Publication No. 2012/0121551 discloses that RNAs consisting of four nucleotides can promote immune responses by inducing the activation of interferon-α.
The RNAs disclosed above have the common feature that they have a triphosphate group at the 5′-end. It is known that an RNA which does not contain a cap but has a triphosphate group at the 5′-end can activate the expression of interferon by binding to intracellular retinoic acid-inducible gene-I (RIG-I) protein.
The present inventors have endeavored diligently to find a substance which can increase the expression of interferon-β or interferon stimulated gene 56 (ISG56) expressed by interferon-β, and surprisingly and unexpectedly discovered that an RNA oligonucleotide which does not have a triphosphate group at the 5′-end can also increase the expression of interferon-β or ISG56 if the RNA oligonucleotide has a specific sequence and structure, and thus can be used as an immune system enhancer.